This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/268,059 filed Feb. 13, 2001.
This invention describes a new process for the preparation of diethylenetriaminepentaacetic acid-monoamides (DTPA-monoamides) Monoamides of DTPA are described extensively in the literature. They are used as complexing agents for metal complexes, which have come to be used in imaging diagnosis. Thus, for example, the compound 3,6-bis(carboxymethyl)-9-(10-carboxydecylcarbamoyl-methyl)-3,6,9-triazaundecanoic acidxe2x80x9cmono-puchelxe2x80x9d is described in EP 450 742 as a potential liver contrast medium. Other monoamides of DTPA for visualizing organs are found in WO 95/27705, EP 529 175, WO 95/33494. Aromatic amides for liver diagnosis (MRI) were described by the Green Cross Company in EP 603 403, U.S. Pat. Nos. 5,453,264 and 5,575 986. In addition, other compound classes, such as, e.g., blood pool contrast media, were described (polylysine-DTPA, EP 331 616, dendrimers EP 430 863), which contain monoamides of DTPA.
In the above-mentioned bibliographic references as well as in special process patents, different methods for the production of: monoamides (starting from DTPA) were described, as in U.S. Pat. No. 5,021,571 or in EP 263 059, formula diagram 1:
The thus obtained monoamides are obtained in a total of six stages. The total yield is relatively low, since the yield of intermediate product (4) is greatly reduced by the partial saponification of the ester groups and the subsequent chromatography.
Other authors describe the production of DTPA tetraesters (U.S. Pat. No. 5,412,148, WO 94/03593, DE 19508058, DE 19507819, U.S. Pat. No. 6080785), in which compounds of general formula (8) 
have to be produced by longer synthesis sequences (in some cases more than five stages). The compounds of general formula (8) are converted into the corresponding active esters of acid and then reacted with an amine HN R1R2 to form the protected monoamides of formula (9) 
The subsequent ester saponification and acidic working-up yield the desired monoamides with free carboxylic acids. A disadvantage to both above-described processes is the fact that ester groups that can be contained in the amine of general formula R1R2 are also saponified by the downstream saponification step. The use of t-butyl esters or benzyl esters is also problematical in nature, since in the case of acidic or reductive cleavage, radicals R1 and R2 are attacked.
Krejcarek follows another method. Krejcarek starts from the DTPA, produces a pentaamonium salt and reacts the latter with one equivalent of chloroformic acid ester to form the mono-mixed anhydride of DTPA and then with one amine [Krejcarek and Tucker, Biochem. Biophys. Res. Commun. 77, 581 (1977), WO 91/05762]. It is disadvantageous in this process that it cannot be determined whether the amide formation takes place on one of the terminal acetic acids or on the central acetic acid. In addition, the high accumulation of by-products is disadvantageous in this process. Five equivalents of amine salt must be removed, four of which were not involved in the activation of that of the carbonyl group.
Processes that start from bisanhydride of DTPA (2) are also known from the patent literature: 
The selective conversion of the bisanhydride of DTPA (2) to form monoamides by adding one equivalent of water, which presumably converts monoanhydride (10), was described in the Patents (U.S. Pat. Nos. 5,559,214, 5,871,710, 5,593,658, EP 451 824). 
Hnatowich has already described the immediate reaction of bisanhydride (2) with amines in aqueous buffer (U.S. Pat. No. 4,479,930).
It is disadvantageous that large excesses of bisanhydride are necessary to produce a selective reaction, and the saponification in water is also a problem. Reactions of bisanhydride (2) in DMF with the addition of pyridine or another base were also described (U.S. Pat. No. 5,571,498, WO 95/33494, WO 96/16679). It is problematical in such reactions that they are performed at an elevated temperature (50-100xc2x0 C.), which is disadvantageous for sensitive amines, and that they show very low selectivities relative to the formation of the monoanhydride. Even if excess (2-5 equivalents) bisanhydride (2) relative to HN R1R2 is used, the main product in all cases is the bisamide (11) 
The monoamide that is formed in the first step obviously has a higher solubility and is therefore more reactive than the bisanhydride that is present in excess and is preferably reacted off. The latter is observed in solvents such as DMF, DMSO, formamide. In the case of reactions of less than 50xc2x0 C., e.g., room temperature, the formation of (11) is observed almost exclusively.
Based on the above-described drawbacks, a need for a new process for the production of monoamides existed, in which
1) Amines can be reacted with sensitive groups (esters, easily saponifying, reducing, temperature-sensitive groups)
2) A higher mono/diamide selectivity is achieved
3) A higher yield of mono-amide is achieved
4) A simple reaction scheme and working-up is achieved.
These requirements are met by this process.
The invention relates to a process for the production of monoamides of DTPA of general formula (I) 
in which
n stands for numbers 1 or 2,
A stands for, when n=1, a primary, secondary, aliphatic, aromatic or araliphatic monoamine that is reduced by a hydrogen atom on a nitrogen atom, or for, when n=2, a primary, secondary, mixed primary/secondary, aliphatic, aromatic, araliphatic or mixed aliphatic/aromatic/araliphatic diamine that is reduced in each case by a hydrogen atom on the two nitrogen atoms, comprising the DTPA-bisanhydride of formula (2) 
is dissolved in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) or mixtures thereof with the addition of an inorganic or organic solubilizer in homogeneous solution, with the addition of an auxiliary base with a monoamine (n=1) or diamine (n=2) of general formula II
A(H)nxe2x80x83xe2x80x83(II) 
in which n and A have the above-mentioned meaning, and is reacted at temperatures of 10-70xc2x0 C. for a reaction time of 1-24 hours.
The solubilizer is used in amounts of 1-10, preferably 2-5 equivalents, relative to the DTPA-bisanhydride (2). The homogeneous solution that comprises the DTPA-bisanhydride (2) and the solubilizer in DMSO, DMF or mixtures thereof that is obtained by heating (up to 150xc2x0 C.) is allowed to cool to the desired reaction temperature and then mixed with amine II, and is optionally dissolved in a solvent, such as, e.g., DMSO, DMF, pyridine, dioxane, tetrahydrofuran or mixtures thereof. A reaction temperature of 15-50xc2x0 C. and a reaction time of 3-8 hours are preferred.
In addition to ammonia (in most cases dissolved in a solvent), amines of natural or synthetic origin are used as amines: primary, secondary, aliphatic, aromatic, araliphatic monoamines and diamines, whereby in the case of diamines, mixed primary/secondary or mixed aliphatic/aromatic/araliphatic diamines can occur. Amines of natural origin occur, i.a., from the classes of steroids, alkaloids, peptides, amino acids, nucleotides, nucleosides, porphyrins and carbohydrates.
Especially preferred are 4-Decylaniline, 11-Aminoundecanoic acid ethyl ester, Mesoporphyrin IX-13,17-dihydrazide and Cu-Mesoporphyrin IX-13,17-dihydrazide
The auxiliary base can either be introduced or added together with the amine A(H)n. It is also possible to use the amines in the form of their salts. In this case, however, excess auxiliary base is necessary. In cases where DMSO is used as a solvent, the following solubilizers are used:
In cases where DMF is used as a solvent, imidazole is used as a solubilizer. As an auxiliary base, organic bases such as pyridine, triethylamine, N-ethyl-morpholine and imidazole are preferably used. DTPA-bisanhydride can be reacted at concentrations of up to 30%. It has also proven advantageous to increase the amount of solubilizer at concentrations of between 20-30%. For working-up, some water is added (1 equivalent and more), either concentrated by evaporation in a vacuum or else precipitated with a solvent such as diethyl ether, acetone, methyl-t-butyl ether (MTB), diisopropyl ether, tetrahydrofuran (THF) or mixtures of the latter, and the precipitate is filtered off. Then, after dissolution and adjustment of the pH, the desired product can be purified chromatographically by crystallization, by ion-exchange chromatography, by chromatography on silica gel or RP-material.
In some cases, it has proven advantageous to dry the above-obtained precipitate, to make a determination of HPLC purity and to go into the next stage with the crude product (e.g., when complexing with metals).
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.